U.S. patent number 6,733,782 [Application Number 09/890,427] was granted by the patent office on 2004-05-11 for core tablet for controlled release of gliclazide after oral administration.
This patent grant is currently assigned to Les Laboratories Servier. Invention is credited to Bruno Huet De Barochez, Louis Martin, Patrick Wuthrich.
United States Patent |
6,733,782 |
Huet De Barochez , et
al. |
May 11, 2004 |
Core tablet for controlled release of gliclazide after oral
administration
Abstract
The invention relates to a matrix tablet for the prolonged
release of gliclazide which ensures continuous and consistent
release of the active ingredient after administration by the oral
route, the release being insensitive to variations in the pH of the
dissolution medium.
Inventors: |
Huet De Barochez; Bruno (Ingre,
FR), Wuthrich; Patrick (Orleans, FR),
Martin; Louis (Olivet, FR) |
Assignee: |
Les Laboratories Servier
(Neuilly-sur-Seine, FR)
|
Family
ID: |
9541429 |
Appl.
No.: |
09/890,427 |
Filed: |
July 31, 2001 |
PCT
Filed: |
October 15, 1999 |
PCT No.: |
PCT/FR99/02520 |
PCT
Pub. No.: |
WO00/18373 |
PCT
Pub. Date: |
April 06, 2000 |
Foreign Application Priority Data
|
|
|
|
|
Feb 1, 1999 [FR] |
|
|
99 01082 |
|
Current U.S.
Class: |
424/464; 424/468;
424/469; 424/488; 424/484; 424/470 |
Current CPC
Class: |
A61P
5/00 (20180101); A61K 9/2018 (20130101); A61K
31/64 (20130101); A61P 3/00 (20180101); A61P
3/10 (20180101); A61K 9/2054 (20130101); A61P
3/12 (20180101); A61K 9/2059 (20130101) |
Current International
Class: |
A61K
9/20 (20060101); A61K 31/64 (20060101); A61K
009/20 (); A61K 009/22 (); A61K 009/26 (); A61K
009/14 () |
Field of
Search: |
;424/488,475,468,469,470,458,464,484 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Page; Thurman K.
Assistant Examiner: Sheikh; Humera N.
Attorney, Agent or Firm: The Firm of Hueschen and Sage
Parent Case Text
This application is a 371 of PCT/FR 99/02520 filed Oct. 15, 1999
Claims
What is claimed is:
1. A Matrix tablet for the prolonged release of gliclazide,
characterized in that it comprises at least the combination of a
cellulose polymer compound and a glucose syrup, that combination
enabling control of the prolonged release of gliclazide and
enabling insensitivity of the dissolution kinetics of gliclazide to
variations in pH.
2. A Gliclazide matrix tablet according to claim 1, characterized
in that the cellulose polymer compound comprises at least one
hydroxypropyl methylcellulose.
3. A Gliclazide matrix tablet according to claim 1, characterized
in that the cellulose polymer compound comprises a mixture of two
hydroxypropyl methylcelluloses of different viscosity.
4. A Gliclazide matrix tablet according to claim 1, characterized
in that the cellulose polymer compound comprises a mixture of
hydroxypropyl methylcellulose of viscosity 4000 cP and
hydroxypropyl methylcellulose of viscosity 100 cP.
5. A Gliclazide matrix tablet according to claim 1, characterized
in that the glucose syrup is maltodextrin.
6. A Gliclazide matrix tablet according to claim 1, characterized
in that the percentage of cellulose polymer compound is from 10 to
40% of the total weight of the tablet.
7. A Gliclazide matrix tablet according to claim 1, characterized
in that the percentage of cellulose polymer compound is from 16 to
26% of the total weight of the tablet.
8. A Gliclazide matrix tablet according to claim 1, characterized
in that the percentage of glucose syrup is from 2 to 20% of the
total weight of the tablet.
9. A Gliclazide matrix tablet according to claim 1, characterized
in that the percentage of glucose syrup is from 4 to 10% of the
total weight of the tablet.
10. A Gliclazide matrix tablet according to claim 1, characterized
in that calcium hydrogen phosphate dihydrate is used as
diluent.
11. A Gliclazide matrix tablet according to claim 1, characterized
in that the percentage of diluent is from 35 to 75% of the total
weight of the tablet.
12. A Gliclazide matrix tablet according to claim 1, characterized
in that the percentage of diluent is from 45 to 60% of the total
weight of the tablet.
13. A Gliclazide matrix tablet according to claim 1, characterized
in that the amount of gliclazide is from 12 to 40% of the total
weight of the tablet.
14. A Gliclazide matrix tablet according to claim 1, characterized
in that it contains a total amount of gliclazide of 30 mg.
15. A Gliclazide matrix tablet according to claim 1, characterized
in that it contains a total amount of gliclazide of 60 mg.
16. A Gliclazide matrix tablet according to claim 1, characterized
in that the percentages of cellulose polymer compound and glucose
syrup make possible a constant gliclazide release profile for a
dissolution medium pH ranging from 6 to 8.
17. A Gliclazide matrix tablet according to claim 1, characterized
in that the percentages of cellulose polymer compound and of
glucose syrup make possible the release of 50% of the total amount
of gliclazide by a time from 4 to 6 hours after administration.
18. A Gliclazide matrix tablet according to claim 1, characterized
in that the percentages of cellulose polymer compound and of
glucose syrup enable prolonged release of gliclazide that results
in humans in blood levels of from 400 to 700 ng/ml 12 hours at most
after a single administration of the tablet by the oral route.
19. A Process for the preparation of a matrix tablet according to
claim 1, characterized in that there are used both a wet
granulation technique and a direct compression technique,
comprising the following steps: STEP A: Mixture of gliclazide,
maltodextrin and calcium hydrogen phosphate dihydrate, followed by
wetting of that mixture with purified water, the resulting wet mass
is then granulated, dried and subsequently classified to obtain a
granulate having physical characteristics that enable good filling
of the moulds of a rapid-compression machine STEP B: Mixture of the
granulate obtained in Step A with hydroxypropyl methylcellulose
STEP C: Lubrication of the mixture obtained in Step B with
colloidal silica and magnesium stearate STEP D: Compression of the
lubricated mixture obtained in Step C using a rotary compression
machine to obtain tablets having a hardness, measured by diametric
crushing, of from 6 to 10 daN.
20. A Gliclazide matrix tablet according to claim 1 for use in the
treatment of diabetes.
Description
FIELD OF THE INVENTION
The present invention relates to a matrix tablet that enables the
prolonged release of gliclazide, the release being insensitive to
variations in the pH of the dissolution medium, and that ensures
regular and continuous blood levels after absorption of the galenic
form by the oral route.
PRIOR ART OF THE INVENTION
Gliclazide, a compound of formula (I): ##STR1##
is a sulphonylurea compound having an antidiabetic property at the
doses usually administered to humans.
Gliclazide has hitherto been administered by the oral route in the
form of tablets containing a dose of 80 mg. The usual average
prescription is two tablets per day in two administrations, but may
vary from 1 to 4 tablets per day in several administrations
depending upon the severity of the diabetes.
One of the aims of the present invention was to obtain an oral form
that can be administered in a single daily administration. On the
one hand this makes it easier for the patient to use and, on the
other hand, it enables better compliance with the treatment.
Another aim of the invention was that the oral form should have
prolonged release. Indeed, in certain patients an immediate-release
form can result in high short-term concentrations in the blood. A
prolonged-release form makes it possible for such peaks in the
blood to be avoided and enables a consistent concentration in the
blood to be obtained in humans. This makes it possible to reduce
the undesirable effects that may occur as a result of the "peak
effect", which are accompanied by hydroelectrolytic- and
metabolic-type disorders associated with variations in the plasma
levels of the active ingredient.
The main aim of the invention was to obtain an oral form in which
the rate of release of the active ingredient is controlled and
reproducible. In fact, in the current form the dissolution of the
active ingredient varies greatly according to pH. This
characteristic, associated with gliclazide itself, poses absorption
problems for the active ingredient. The phenomenon of the
solubility of the active ingredient varying according to pH is
shown in FIG. 1 (attached). The solubility is very weak at acid pHs
and increases as pH rises.
It was thus important, for this active ingredient, to develop a new
galenic form that makes possible gliclazide release that is
independent of the pH of the dissolution medium.
DISCLOSURE OF THE INVENTION
More especially, the present invention describes a hydrophilic
matrix that can be administered by the oral route and that enables
prolonged and controlled release of the active ingredient,
gliclazide, without the pH influencing the in vitro dissolution
kinetics of the said matrix.
That form for the prolonged release of gliclazide, for use in the
treatment of diabetes, makes it possible to provide more consistent
plasma levels and smaller C.sub.max -C.sub.min variations. The rate
of release must be reproducible and must be correlated with blood
concentrations observed after administration.
Among the mechanisms that can be used to control the diffusion of a
soluble active ingredient one principal mechanism may be selected,
that being the diffusion of the active ingredient through a gel
formed after the swelling of a hydrophilic polymer placed in
contact with the dissolution liquid (in vitro) or with
gastro-intestinal fluid (in vivo).
Many polymers have been described as being capable of enabling such
a gel to be formed. The main polymers are cellulose compounds,
especially cellulose ethers, such as hydroxypropyl cellulose,
hydroxyethylcellulose, methylcellulose and hydroxypropyl
methylcellulose and, among the various commercial grades of those
ethers, those of relatively high viscosity. It should be noted that
the systems described do not have the theoretical possibility of
allowing a zero order to be obtained in the release kinetics
equation.
The production processes currently used for the production of such
matrix tablets are either direct compression, after mixing the
various excipients and the active ingredient(s), or wet
granulation.
The gliclazide matrix tablet described in the present invention
combines in a novel manner at least one cellulose polymer compound
and a glucose syrup (maize starch hydrolysate), enabling release of
the active ingredient that is perfectly prolonged and
controlled.
The controlled release is linear for a period of more than eight
hours and is such that 50% of the total amount of gliclazide has
been released between 4 and 6 hours after administration. Moreover,
the matrix tablet according to the invention enables prolonged
release of gliclazide that results in humans in blood levels of
from 400 to 700 ng/ml 12 hours at most after a single
administration by the oral route of a tablet containing a dose of
30 mg of gliclazide, and in blood levels of from 250 to 1000 ng/ml
after a daily administration of a tablet containing a dose of 30 mg
of gliclazide.
The unit dosage may vary according to the age and weight of the
patient and the nature and severity of the diabetes. It generally
ranges from 30 to 120 mg, in a single administration, for a daily
treatment. The percentage of gliclazide in the matrix tablet is
from 12 to 40% of the total weight of the tablet. According to an
advantageous embodiment of the invention, the said tablet contains
a dose of 60 mg of gliclazide. An especially preferred embodiment
of the invention is the provision of tablets containing a dose of
30 mg of gliclazide. In those very advantageous examples of the
invention, the unit dosage, which ranges from 30 to 120 mg, for a
single daily administration, corresponds to the absorption of from
1 to 4 tablets containing a dose of 30 mg or of 1 or 2 tablets
containing a dose of 60 mg. The matrix tablet as described by the
Applicant on the one hand makes it possible to have an oral form
that can be administered in a single daily administration and, on
the other hand, surprisingly and especially advantageously, makes
it possible to reduce the amount of active ingredient in each
tablet without the plasma concentrations of gliclazide being
modified or altered. The formulation hitherto in existence
contained a dose of 80 mg of gliclazide.
The specific combination of the compounds described above also,
surprisingly, makes it possible for the in vitro dissolution
kinetics of the said matrix to be unaffected by the pH although the
solubility of the active ingredient varies according to that same
pH. This point is illustrated by FIG. 2 (attached), which shows
that a matrix as formulated is insensitive to variations in pH over
a range of from 6.2 to 7.4 occurring in the intestinal environment.
Thus, within a pH range of from 6 to 8 corresponding to the rising
part of the curve shown in FIG. 1 (attached), it can be seen that
the release profile of the active ingredient at between 0 and 12
hours is the same, irrespective of the pH of the dissolution medium
of the matrix tablet containing the said active ingredient.
Thus, by the characteristic combination of at least one cellulose
polymer compound and a glucose syrup, the Applicant has created a
hydrophilic matrix that is innovative in terms of both its
composition and its function since, in particular, it enables the
active ingredient that it contains, gliclazide, to be released in a
prolonged and controlled manner, irrespective of the pH conditions
of the dissolution medium.
The cellulose polymer compound used in that hydrophilic matrix is a
high-viscosity cellulose either. Advantageously, the cellulose
ether is a hydroxypropyl methylcellulose, preferably a mixture of
two hydroxypropyl methylcelluloses of different viscosity. The
other compound in the composition of the said matrix is a glucose
syrup and, advantageously, maltodextrin is used, which is a glucose
syrup having an equivalent degree of dextrose (ED) of from 1 to 20.
The combination of those two types of compounds on the one hand
enables a formulation to be obtained in which the release profile
of the active ingredient is insensitive to variations in the pH of
the dissolution medium and, on the other hand, enables perfect
control of the release kinetics to be obtained. The percentage of
cellulose polymer compound is from 10 to 40% of the total weight of
the tablet and, according to an especially advantageous embodiment,
from 16 to 26% of the total weight of the tablet. The percentage of
glucose syrup is from 2 to 20% of the total weight of the tablet
and, preferably, from 4 to 10% of the total weight of the
tablet.
Various excipients can also be added to complete the formulation.
Among the conventionally used diluents, preference is given to the
use of calcium hydrogen phosphate dihydrate, which enables improved
granule fluidity and improved granule compressibility to be
obtained. Moreover, calcium hydrogen phosphate dihydrate is able to
slow down the dissolution kinetics, that characteristic making it
possible to use smaller amounts of hydroxypropyl methylcellulose to
control the dissolution profile of the active ingredient. The
percentage of calcium hydrogen phosphate dihydrate is from 35 to
75% of the total weight of the tablet, preferably from 45 to 60% of
the total weight of the tablet. Among the lubricants there may be
mentioned by way of example magnesium stearate, stearic acid,
glycerol behenate and sodium benzoate and, among the flow agents,
preference is given to the use of anhydrous colloidal silica.
The present invention relates also to the preparation of the matrix
tablet. Wet granulation is carried out by mixing the active
ingredient, glucose syrup and calcium hydrogen phosphate dihydrate,
and then wetting the mixture. This first step enables the creation
around the active ingredient of a hydrophilic environment that
promotes its good dissolution, and also enables the provision of a
unit dose that is as consistent as possible. In a second step, the
granulate obtained above is mixed with the cellulose ether. If
desired, the cellulose ether can be granulated directly with the
active ingredient in the first step. The mixture is then lubricated
by the addition of colloidal silica and magnesium stearate. The
final lubricated compound is then compressed.
The following Examples illustrate the invention but do not limit it
in any way.
The preparation of prolonged-release tablets that can be
administered by the oral route is carried out according to the
following production process:
STEP A:
Mixture of gliclazide, maltodextrin and calcium hydrogen phosphate
dihydrate, followed by wetting of that mixture with purified water.
The resulting wet mass is then granulated, dried and subsequently
classified to obtain a granulate having physical characteristics
that enable good filling of the moulds of a rapid-compression
machine.
STEP B:
Mixture of the granulate obtained in Step A with hydroxypropyl
methylcellulose.
STEP C:
Lubrication of the mixture obtained in Step B with colloidal silica
and magnesium stearate.
STEP D:
Compression of the lubricated mixture obtained in Step C using a
rotary compression machine to obtain tablets having a hardness,
measured by diametric crushing, of about from 6 to 10 daN.
EXAMPLE 1
Example 1 shows the influence of maltodextrin on the in vitro
release kinetics. The amount of maltodextrin ranges from 7.5 to 15
mg per tablet, thus constituting from 4 to 10% of the total weight
of the tablet. The amount of hydroxypropyl methylcellulose remains
constant and the amount of diluent, calcium hydrogen phosphate
dihydrate, is adjusted to obtain tablets having a constant weight
of 160 mg. Production is carried out according to the procedure
described in Steps A to D.
TABLE 1 Unit formulation of the tablets (in mg per tablet) and
characteristics Batches Constituents LP1 LP2 Gliclazide 30 30
Calcium hydrogen phosphate dihydrate 87.4 79.9 Maltodextrin (*) 7.5
15 Hydroxypropyl methylcellulose 34 34 Magnesium stearate 0.8 0.8
Colloidal silica 0.32 0.32 Final weight 160 160 Active ingredient
dissolved at 8 h (%) 73 84 (*) the amount of maltodextrin
corresponds to 6 or 12% of the amount of granulated material
(active ingredient + calcium hydrogen phosphate dihydrate +
maltodextrin).
The amount of maltodextrin, at a constant hydroxypropyl
methylcellulose weight, influences the release of the active
ingredient for a period of more than 4 hours. The dissolution curve
is linearised by increasing the amount of maltodextrin as shown in
FIG. 3.
EXAMPLE 2
Example 2 shows the influence of hydroxypropyl methylcellulose on
the in vitro release kinetics. The amount of hydroxypropyl
methylcellulose ranges from 26 to 42 mg, thus constituting from 16
to 26% of the total weight of the tablet. Production is carried out
according to the procedure described in Steps A to D.
TABLE 2 Unit formulation of the tablets (in mg per tablet) Batches
Constituents LP3 LP4 Gliclazide 30 30 Calcium hydrogen phosphate
dihydrate 79.87 94.91 Maltodextrin (*) 7.01 7.97 Hydroxypropyl
methylcellulose 42 26 Magnesium stearate 0.8 0.8 Colloidal silica
0.32 0.32 Final weight 160 160 Active ingredient dissolved at 4 h
(%) 35 52 (*) the amount of maltodextrin corresponds to 6% of the
amount of granulated material (active ingredient + calcium hydrogen
phosphate dihydrate + maltodextrin).
The amount of hydroxypropyl methylcellulose in the hydrophilic
matrix strongly influences the release of the active ingredient as
shown in FIG. 4.
EXAMPLE 3
Example 3 shows the influence of the grade of hydroxypropyl
methylcellulose used on the in vitro release kinetics. In each of
the batches, the total weight of hydroxypropyl methylcellulose is
constant and the relative amount of each of the hydroxypropyl
methylcelluloses of different viscosity is varied, thereby making
it possible to obtain a slow dissolution batch (LP5) and a rapid
dissolution batch (LP7), compared with the reference batch
(LP6).
TABLE 3 Unit formulation of the tablets (in mg) Batches
Constituents LP5 LP6 LP7 Gliclazide 30 30 30 Calcium hydrogen
phosphate dihydrate 83.64 83.64 83.64 Maltodextrin (*) 11.24 11.24
11.24 Hydroxypropyl methylcellulose 4000 cP 24 16 8 Hydroxypropyl
methylcellulose 100 cP 10 18 26 Magnesium stearate 0.8 0.8 0.8
Colloidal silica 0.32 0.32 0.32 Final weight 160 160 160 Active
ingredient dissolved at 4 h (%) 33 46 58 (*) the amount of
maltodextrin corresponds to 9% of the amount of granulated material
(active ingredient + calcium hydrogen phosphate dihydrate +
maltodextrin).
The curves of FIG. 5 show clearly that the dissolution kinetics of
the active ingredient are influenced not only by the total amount
of hydroxypropyl methylcellulose used in the hydrophilic matrix but
also by the grade of the hydroxypropyl methylcellulose used as
shown in FIG. 5.
The gliclazide plasma kinetics are measured in 12 subjects after a
single administration of tablet LP6. The mean plasma concentration
is given in FIG. 6.
The curve of FIG. 6 shows a matrix-type dissolution profile
(continuous release of the active ingredient) with monophase plasma
kinetics.
EXAMPLE 4
Example 4 shows that the in vitro release kinetics of a tablet
containing a dose of 60 mg are similar to that of a tablet
containing a dose of 30 mg (batch LP6) for matrix tablets
containing the same doses of hydroxypropyl methylcellulose and of
maltodextrin. The in vitro dissolution kinetics is shown in FIG.
7.
TABLE 4 Unit formulation of the tablets (in mg) Constituents
Batches LP8 Gliclazide 60 Calcium hydrogen phosphate dihydrate
53.64 Maltodextrin 11.24 Hydroxypropyl methylcellulose 34 Anhydrous
colloidal silica 0.32 Magnesium stearate 0.8 Final weight 160 mg
Active ingredient dissolved at 4 h (%) 45
DESCRIPTION OF THE DRAWINGS
FIG. 1 represents the phenomenon of the solubility of the active
ingredient varying according to pH.
FIG. 2 represents the influence of the pH of the dissolution medium
on the release profile of the active ingredient.
FIG. 3 represents the curves for the dissolution kinetics of the
two formulations used in Example 1.
FIG. 4 represents the curves for the dissolution kinetics of the
two formulations used in Example 2.
FIG. 5 represents the curves for the dissolution kinetics of the
three formulations used in Example 3.
FIG. 6 represents the mean plasma concentration of Example 3.
FIG. 7 represents the in vitro dissolution kinetics of Example
4.
* * * * *